The overall objective of this proposal is to develop an orally available small molecule for the prevention and treatment of diabetic retinopathy - the leading cause of new blindness among adults in America. During Phase I of this proposal, we demonstrated that the administration of the anti-glycation agent, EXO-226, to rodent models of diabetes lowered the concentration of glycated albumin in the plasma and prevented the morphological abnormalities characteristic of diabetic retinopathy and nephropathy. During Phase II, those studies of EXO-226 administration to diabetic rodents will be extended to provide further proof of concept that lowering of plasma glycated albumin is effective in the prevention or reversal of diabetic retinal disease. Structural analogs of EXO-226 will be synthesized to produce compounds in which anti-glycation activity is maximized and cyclo-oxygenase activity is minimized (to prevent gastrointestinal irritation). The lead candidate analogs will be studied for absorption, biodistribution and toxicology in rodents. Based on those studies, appropriate doses of the analogs will be given to diabetic rodents to determine their anti-glycation activity and for their ability to prevent or reverse the morphological changes characteristic of diabetic retinopathy in these models. Finally, EXO-226 will be administered to diabetic human subjects over a 6 months period to determine whether anti-glycation therapy will reduce the leakage of substances from the retinal vasculature that represents the earliest functional retinal abnormality of diabetic retinopathy. PROPOSED COMMERCIAL APPLICATION The research and development described in this project is expected to lead to new chemical entities for the prevention/treatment of diabetic retinopathy.